BackgroundIndividuals aged 80 and older face a notably increased risk of venous thromboembolism (VTE) and mortality after SARS-CoV-2 infection. Clinical guidelines recommend routine pharmacological thromboprophylaxis, yet its application in oldest-old patients remains insufficiently studied. AimsTo assess the efficacy and safety of low-molecular-weight heparin (LMWH) thromboprophylaxis in hospitalized COVID-19 patients aged 80 years and older. MethodsWe conducted a multicenter, prospective cohort study enrolling in-hospital COVID-19 patients aged >= 80 years from six tertiary hospitals in China between December 2022 and January 2023. The clinical outcomes were VTE, all-cause mortality and bleeding events. Patients were followed up for 3 months after discharge. Multivariate Cox regression models were used to identify risk factors and evaluate the impact of LMWH prophylaxis on clinical outcomes. ResultsAmong 1526 patients aged >= 80 years, 41.6% received LMWH prophylaxis. LMWH prophylaxis significantly reduced VTE risk by 50% (HR 0.50, 95% CI 0.33-0.75) and mortality risk by 20% (HR 0.80, 95% CI 0.65-0.99), without increasing bleeding risk (HR 0.90, 95% CI 0.60-1.34). Male, history of stroke, critical illness on admission and hemoglobin < 90 g/L were identified as risk factors of bleeding. LMWH prophylaxis remained effective in preventing VTE and demonstrated favorable safety particularly in male patients and patients with hemoglobin < 90 g/L. Discussion and conclusionLMWH may be safe and effective for thromboprophylaxis in the oldest-old COVID-19 patients, even in patients with high bleeding risk. Further studies are needed to verify our findings.